piperidines and Vascular-Diseases

The realisation that serotonin plays a role not only in the carcinoid syndrome but also in migraine, nociception, dumping syndrome, vascular disease and hypertension, has led to an enormous amount of activity in search of serotonin antagonists. Numerous such pharmacological agents have been identified but only few have found their way into clinical use. All of them are competitive serotonin inhibitors, in that they vie for the same receptor as the amine itself and are thus able to block its action as well as imitate its effects. By far the widest use of such inhibitors is in the prevention of migraine, where they have effectively eliminated the dread of an attack from the life of the majority of patients. Whilst useful in the control of diarrhea in patients with carcinoid and dumping syndromes, their role in these diseases is limited. However, the possible role of serotonin in hypertension and nociception opens new avenues in the use of existing serotonin antagonists and calls for the discovery of a new generation of such pharmacological agents for the control of these conditions.

Topics: Cyproheptadine; Depression; Ergotamine; Humans; Hypertension; Ketanserin; Lisuride; Methysergide; Mianserin; Migraine Disorders; Piperidines; Pizotyline; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Vascular Diseases

Impaired glucose tolerance (IGT) is associated with increased cardiovascular risk. The pathophysiological mechanisms linking post-challenge hyperglycemia to accelerated atherosclerosis, however remain to be elucidated.. A prospective, open, randomised, cross-over study was performed to investigate the effect of 2 mg repaglinide on hyperglycemia and endothelial function during an oral glucose tolerance test (75 g glucose) in 12 subjects with diagnosed IGT. Blood samples for determination of plasma glucose were drawn fasting, 1 and 2 hours after glucose ingestion. Endothelial function was assessed by measuring flow-mediated dilatation (FMD) of the brachial artery with high-resolution ultrasound.. Administration of repaglinide resulted in a significant reduction of plasma glucose at 2 hours (172.8+/-48.4 vs. 138.3+/-41.2 mg/dl; p < 0.001). The flow-mediated dilatation (FMD) 2 hours after the glucose-load was significantly reduced in comparison to fasting in the control group (6.21+/-2.69 vs. 7.98+/-2.24 %; p = 0.028), whereas after theadministration of repaglinide the FMD was not significantly different to fasting values (7.24+/-2.57 vs. 8.18+/-2.93 %; p = n.s.). Linear and logistic regression analysis revealed that only the change of glucose was significantly correlated to the change of FMD observed (p < 0.001). Regression analysis after grouping for treatment and time confirmed the strong negative association of the changes of plasma glucose and FMD and indicate that the effect of repaglinide observed is based on the reduction glycemia.. In subjects with IGT, the endothelial dysfunction observed after a glucose challenge is related to the extent of hyperglycemia. Reduction of hyperglycemia by repaglinide reduces endothelial dysfunction in a glucose dependent manner.

Topics: Aged; Blood Glucose; Carbamates; Cross-Over Studies; Endothelium, Vascular; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Vascular Diseases

Topics: Adult; Aged; Clinical Trials as Topic; Drug Evaluation; Ear; Ear Diseases; Female; Humans; Male; Middle Aged; Piperidines; Vascular Diseases; Vasodilator Agents

STING-associated vasculopathy with onset in infancy (SAVI) is a new rare auto-inflammatory disease. The purpose of this study is to report new cases and summarize the manifestations and outcome of SAVI.. We made a retrospective analysis of three pediatric patients diagnosed with SAVI between March 2016 and July 2018 in Beijing Children's Hospital.. Three patients comprised one boy and two girls. The median age of onset was 4 months. All patients had the same de novo heterozygous mutation (c.463G>A, p. V155M) of TMEM173. All patients presented with interstitial lung disease and one coexisted with diffuse alveolar hemorrhage. Rashes were presented in two patients. Other clinical manifestations include febrile attacks, failure to thrive, arthritis, myositis, cerebrovascular involvement, ureteral calculus, gastroesophageal reflux, and malnutrition. Ground-glass opacities were the most common features of chest computed tomography, followed with cysts and reticular opacities. Transbronchial lung biopsy was performed in one patient revealing pulmonary vasculitis. Skin biopsy was performed in one patient with changes of vasculitis. All patients were treated with corticosteroids and two patients received combined treatment of tofacitinib. The therapeutic effects of tofacitinib were limited on interstitial lung disease in both patients and were poor on rashes in one patient. One patient under the treatment of tofacitinib died.. New clinical aspect of diffuse alveolar hemorrhage is first reported to be associated with SAVI. Unsatisfactory therapeutic effects of tofacitinib are observed in this study and further evaluations are needed.

Topics: Child, Preschool; Female; Hemorrhage; Humans; Infant; Inflammation; Lung; Lung Diseases, Interstitial; Male; Membrane Proteins; Mutation; Piperidines; Pyrimidines; Retrospective Studies; Skin; Vascular Diseases

Topics: Humans; Livedo Reticularis; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Diseases, Vascular; Skin Ulcer; Vascular Diseases

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia accompanied by impaired vascular and endothelial function. Activation of ATP-sensitive potassium (K. Rats were divided into three groups: control, STZ (65 mg/kg, ip) and STZ + KMUP-1 (5 or 10 mg/kg/day, ip). MA reactivity was measured by dual wire myograph. MA smooth muscle cells (MASMCs) were enzymatically dissociated and the K. STZ decreased MA K. KMUP-1 prevents STZ impairment of MA reactivity, eNOS levels and K

Topics: Animals; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; KATP Channels; Male; Membrane Potentials; Mesenteric Arteries; Myocytes, Smooth Muscle; Nitric Oxide Synthase Type III; Piperidines; Potassium; Rats; Time Factors; Vascular Diseases; Xanthines

Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized.. MRL/lpr lupus-prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice.. Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies.. Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.

Topics: Animals; Female; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Vascular Diseases

Topics: Child; Humans; Male; Membrane Proteins; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Vascular Diseases

Pulmonary vascular remodeling and dysfunction associated to tobacco smoking might pave the way for the subsequent development of pulmonary hypertension. Its prognosis is dreadful and its underlying mechanisms are so far largely unknown in humans. To assess the potential role of endothelin-1 and its receptors in smokers' pulmonary artery vasoactive properties. Endothelium-dependent vasodilation to ACh was assessed in pulmonary vascular rings from 34 smokers and compared with that of 10 nonsmokers. The effects of ET-A (BQ 123) or ET-B (BQ 788) blockers and that of an ET-B activator (sarafotoxin) were evaluated. Endothelin-1 was quantitated by ELISA. Expression of its receptors was quantitated by Western blotting. Smokers exhibited an impaired pulmonary endothelium-dependent vasodilation compared with nonsmokers (P < 0.01). In the former group, 8 of 34 subjects exhibited a marked endothelial dysfunction (ED(+)) whereas 26 (ED(-)) (P < 10(-4)) displayed a vasorelaxation to ACh that was comparable to that of nonsmokers. In ED(+) subjects, ET-A was overexpressed (P < 0.05) and inversely correlated (P < 10(-2)) with the response to ACh. Sarafotoxin significantly improved vasodilation in all subjects (P < 10(-2)). In conclusion, tobacco smoking is associated to an impaired pulmonary vasorelaxation at least partly mediated by an ET-1/ET-A-dependent dysfunction.

Topics: Acetylcholine; Adult; Aged; Antihypertensive Agents; Blotting, Western; Ciprofloxacin; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Smoking; Vascular Diseases; Vasodilation; Vasodilator Agents

Sciatic nerve section in rats evokes chronic hindlimb edema, pain behavior, and hyperalgesia, a syndrome resembling complex regional pain syndrome (CRPS II) in man. Furthermore, there is an increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous limbs of CRPS patients. Now we demonstrate that sciatic nerve section also generates chronic hindlimb warmth, distal articular tenderness, allodynia, and periarticular osteoporosis, sequelae of nerve injury resembling those observed in CRPS. We postulated that facilitated substance P signaling may contribute to these vascular and nociceptive abnormalities and attempted to reverse these changes with the long acting substance P receptor (NK(1)) antagonist LY303870. Hindpaw spontaneous extravasation was inhibited by LY303870. Systemic administration of LY303870 also reversed hindpaw edema and cutaneous warmth. Intrathecal, but not systemic administration of LY303870 reversed soft tissue and articular mechanical hyperalgesia in the hindpaw. Collectively, these data further support the hypothesis that the sciatic nerve transection model closely resembles CRPS and that substance P contributes to the spontaneous extravasation, edema, warmth, and mechanical hyperalgesia observed in this model.

Topics: Animals; Causalgia; Disease Models, Animal; Indoles; Male; Neurokinin-1 Receptor Antagonists; Pain Measurement; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Sciatic Neuropathy; Vascular Diseases

Serotonin is a vasoactive substance that acts on blood vessels and platelets but whose primary action lies in its role as an amplifier for other agents. The aim of this work was to study the effects on blood platelets and erythrocytes of the S2-serotonergic receptor antagonist ketanserin. Twenty-seven patients with untreated hypertension and/or intermittent claudication received a bolus intravenous (i.v.) injection of 10 mg ketanserin followed by 2 mg/h during 3 h i.v. infusion. Platelet function and erythrocyte filterability were studied before and 30 min, 3 h, and 24 h after the bolus injection. The results showed decreases of plasma beta-thromboglobulin and platelet factor 4 levels (p less than 0.001) and platelet aggregation induced by epinephrine plus serotonin (p less than 0.001), whereas ADP-induced aggregation remained unchanged 30 min and 3 h after ketanserin administration. Red cell filterability was decreased (p less than 0.01). There was a tendency toward lower mean arterial blood pressure but heart rate remained unchanged. The dual effect of ketanserin on platelet function and erythrocyte filterability might be of great clinical value in hypertension and peripheral vascular disease in which microcirculatory flow is altered.

Topics: Adult; Aged; Blood Platelets; Erythrocyte Deformability; Erythrocytes; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Platelet Aggregation; Serotonin Antagonists; Vascular Diseases

A new technique consisting of continuous intraarterial infusion of the ultra-short-lived 81mKr for the study of blood flow in patients with severe peripheral vascular disease is described. With the gamma camera high resolution images and typical time activity curves, reflecting local regional blood flow in the feet, could be obtained under resting conditions during reactive hyperemia and administration of vasodilating drugs. Preliminary promising results of Ketanserin, a new selective serotonin antagonist, in patients with impending gangrene and ulcerations are discussed.

Topics: Animals; Arteriosclerosis Obliterans; Cats; Diabetic Angiopathies; Female; Humans; Hyperemia; Ketanserin; Krypton; Leg; Male; Piperidines; Radioisotopes; Radionuclide Imaging; Regional Blood Flow; Serotonin; Serotonin Antagonists; Thromboangiitis Obliterans; Vascular Diseases

Topics: Carbon Monoxide; Humans; Ketotifen; Oxygen; Piperidines; Smoking; Tars; Thiophenes; Vascular Diseases

Topics: Arteries; Humans; Kidney; Muscle Relaxants, Central; Piperidines; Propiophenones; Regional Blood Flow; Vascular Diseases; Veins

Topics: Adolescent; Brain Injuries; Child; Diseases in Twins; Humans; Intellectual Disability; Male; Nitriles; Phenothiazines; Piperidines; Psychomotor Disorders; Tranquilizing Agents; Vascular Diseases; Vomiting

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Autistic Disorder; Autonomic Nervous System; Catatonia; Female; Hallucinations; Humans; Hypnotics and Sedatives; Liver Function Tests; Male; Mental Disorders; Nausea; Neurotic Disorders; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Schizophrenia; Sleep Wake Disorders; Stimulation, Chemical; Sweating; Tremor; Vascular Diseases; Vomiting

Topics: Anticonvulsants; Antihypertensive Agents; Glutethimide; Humans; Pain; Peripheral Arterial Disease; Peripheral Vascular Diseases; Piperidines; Postoperative Care; Postoperative Period; Preoperative Care; Reserpine; Secologanin Tryptamine Alkaloids; Vascular Diseases